title: Computational study of the mechanism of half-reactions in class 1A dihydroorotate dehydrogenase from Trypanosoma cruzi.
abstract: Chagas' disease is considered to be a health problem affecting millions of people in Latin America. This disease is caused by the parasite Trypanosoma cruzi. Recently dihydroorotate dehydrogenase class 1A from Trypanosoma cruzi (TcDHODA) was shown to be essential for the survival and growth of T. cruzi and proposed as a drug target against Chagas' disease. This enzyme catalyzes the oxidation of (S)-dihydroorotate to orotate, with a proposed catalytic cycle consisting of two half-reactions. In the first half-reaction dihydroorotate is oxidized to orotate, with the consequent reduction of the flavin mononucleotide cofactor. In the second half-reaction fumarate is reduced to succinate. The first oxidation half-reaction may occur via a concerted or a stepwise mechanism. Herein, the catalytic mechanism of TcDHODA has been studied using hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) Molecular Dynamics (MD) simulations. The free energy profiles derived from the bidimensional potential of mean force reveal more details for two half-reaction processes.
authors.affiliation: Laborátorio de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará (UFPA), Belém, PA 66075-110, Brazil. nahum@ufpa.br.
authors.forename: Natália de Farias
authors.initials: Nde F
authors.lastname: Silva
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Sergio
authors.initials: S
authors.lastname: Martí
mesh_terms: D055162:Biocatalysis; D000090722:Dihydroorotate Dehydrogenase; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009963:Orotic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory; D055672:Static Electricity; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D000090722:Dihydroorotate Dehydrogenase; C004768:4,5-dihydroorotic acid; D009963:Orotic Acid; D044925:Oxidoreductases Acting on CH-CH Group Donors